Lung disease caused by Respiratory Syncytial Virus (RSV) infection is a significant burden on global human health. Very young children and bone marrow transplant recipients are particularly vulnerable to developing severe lung disease. Current treatments are limited and costly. There are no licensed anti-virals or vaccines specific for RSV currently available to alleviate lung disease caused by RSV infection. The preclinical development of therapeutics to treat RSV infections has been hampered by the lack of easily accessible small animal in vivo models that recapitulate the nature and magnitude of RSV infection and airway pathology of RSV infection of humans. This proposal explores genetically engineered hamsters as new models of RSV infection and disease for pre-clinical testing of RSV therapeutics. Preliminary studies suggest these new hamster models recapitulate the kinetics and airway pathology of RSV infection of human airways. We have taken a rational approach in designing our hamster models. As RSV infection degrades STAT2 to enhance virus replication in human cells, but not rodent cells, we reasoned hamsters, normally only semi- permissive for RSV infection, may become more permissive to infection if deleted of STAT2. Our preliminary studies comparing RSV infection in wild-type versus hamsters deleted of STAT2 (STAT2-/-) confirmed this notion with more robust infection in the upper and lower airways of STAT 2-/- hamsters. These studies also revealed a more significant airway pathology in STAT2-/- hamsters infected by RSV, likely related to the increased infection and replication rates, and with striking similarities to the airway pathology seen in RSV-infected humans. We propose STAT2-/- hamsters provide an authentic small animal model for testing RSV therapeutics. Aim 1 focuses on quantitative assessment of RSV infection and subsequent airway pathology in STAT2-/- hamsters to provide a framework of outcome measures for future testing of new therapeutic approaches. Bone marrow transplant recipients represent the other vulnerable patient population suffering prolonged and more severe RSV infections. The development of potent anti-virals and other approaches to alleviate airway disease are required as this population will likely benefit less from RSV vaccine approaches. By crossing STAT2- /- hamsters with hamsters deleted of RAG2 (RAG2-/-), an important modulator of lymphocyte differentiation, we next generate a hamster model deleted of STAT2 which is also deficient in T and B lymphocytes. Aim 2 focuses on testing whether STAT2 and RAG2 double knockout hamsters develop robust and prolonged RSV infections and more severe airway pathology, thus providing a model of RSV infection in bone marrow transplant recipients. These studies aim to provide the RSV community with more authentic and easily accessible small animal models for pre-clinical testing of RSV therapeutics in two of the most vulnerable patient populations to RSV infection; otherwise healthy children and bone marrow transplant recipients.